bims-proned 2026-07-05 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–07–05
fourteen papers selected by
Verena Kohler, Umeå University

Covalent Modulation of Protein Misfolding and Aggregation Processes in the Context of Neurodegenerative Diseases.
α-Synuclein aggregation landscape from phase separation to neurotoxic intermediates.
Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.
Enrichment and amplification of secreted α-synuclein from cellular model and saliva of patients with synucleinopathies.
Structural dynamics of α-Synuclein: Multi-scale imaging insights into pathological progression across Synucleinopathies.
When mitochondria lose their fold: matrix proteostasis and stress signaling.
Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.
Connexin 50 mediates disease-relevant alpha-synuclein oligomer propagation and neuroinflammation in neurodegenerative disease.
Molecular and environmental drivers of tau post-translational modifications and tau pathology.
TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.
Genetic Code Expansion, Enzymatic Modification, and C-Terminal Labeling Enable Facile Production of Highly Modified α-Synuclein.
Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.
Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.
A new paradigm in Parkinson's disease: kidney-origin α-synuclein pathology driven by PKC signaling and aurothioglucose.

Arch Pharm (Weinheim). 2026 Jun;359(6): e70285

Covalent Modulation of Protein Misfolding and Aggregation Processes in the Context of Neurodegenerative Diseases.

Filippo Basagni, Elena Roggiolani, Anna Minarini, Michela Rosini.

  Misfolded protein aggregates represent major histopathological hallmarks of neurodegenerative diseases, differing in the structural components and brain regions affected. Furthermore, the formed assemblies act as key players in developing and fostering neurotoxic processes, with distinct mechanisms depending on the stage of the amyloid cascade. Particularly, the oligomer intermediates are now considered as the main drivers of neurotoxicity, thus requiring an early antiaggregant therapeutic intervention to achieve a significant neuroprotective efficacy. Among different strategies, direct interaction at early stages preventing aggregation is quite intricate due to the considered undruggability of misfolded monomers. In this context, a covalent approach targeting specific functional nucleophilic residues within disordered proteins can offer an intriguing opportunity to overcome these weaknesses. Therefore, in this review, we outline covalent modulators of misfolding and aggregation processes reported to date, referring to the major misfolded proteins in the neurodegenerative context (i.e., β-amyloid, tau, α-synuclein, and superoxide dismutase 1) to highlight their potential both as valuable pharmacological tools or therapeutic perspectives.

Keywords:  antiaggregating compounds; covalent inhibitor; intrinsically disordered proteins; neurodegenerative diseases; proteinopathies

DOI:  https://doi.org/10.1002/ardp.70285
FEBS Lett. 2026 Jul 01.

α-Synuclein aggregation landscape from phase separation to neurotoxic intermediates.

Silvia Arino, Giuliana Fusco, Alfonso De Simone.

  The aberrant aggregation of α-synuclein (αS) into insoluble amyloid fibrils is a hallmark of Parkinson's disease. Despite recent advances in characterising the properties of mature αS fibrils, the transient and heterogeneous intermediates that underlie cellular toxicity remain largely elusive. Here, we review the mechanistic principles of αS aggregation, focussing on liquid-liquid phase separation (LLPS) as a critical intermediate step. We discuss how the structural evolution of αS within the condensed phase governs the subsequent patterns of cellular dysfunction and pathological propagation. This framework supports an emerging state-centric paradigm in therapeutic discovery, where the physical properties of αS condensates are modulated to mitigate the deleterious effects of its misfolding, offering a new sophisticated alternative to classical inhibition strategies.

Keywords:  amyloid intermediates; liquid–liquid phase separation (LLPS); neurodegeneration; protein condensates; α‐synuclein aggregation

DOI:  https://doi.org/10.1002/1873-3468.70393
Phys Chem Chem Phys. 2026 Jul 02.

Nanoscale morphological and structural analysis of round and donut oligomers formed by C-terminal domain of TDP-43.

Davis Pickett, Yana Purvinsh, Joshua T Skrehot, Daniel Warren, Dmitry Kurouski.

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), limbic predominant age-related TDP-43 encephalopathy (LATE), and Parkinson's disease are associated with an abrupt aggregation of TAR DNA-binding protein 43 (TDP-43). Although molecular mechanisms of this pathological aggregation remain unclear, accumulated evidence suggests that the C-terminus domain (C-terminal domain (CTD)) is the trigger of TDP-43 self-assembly into toxic oligomers and fibrils. While the secondary structure and morphology of protein fibrils have been well documented, very little is known about TDP-43 oligomers. This is primarily because of the transient nature and low concentrations of these protein species. In the current study, we utilize nano-infrared spectroscopy, also known as atomic force microscopy-infrared (AFM-IR) spectroscopy, to investigate the morphology and secondary structure of CTD of TDP-43 oligomers formed at the early and middle stages of protein aggregation. This innovative technique allows us to resolve both morphology and secondary structure of individual protein aggregates. We found that at the early stage of protein aggregation, CTD of TDP-43 formed two morphologically different protein aggregates: donut-like (DO) and round (RO) oligomers. DO yielded fibrillar species, while RO persisted throughout the entire course of CTD TDP-43 self-assembly.

DOI: https://doi.org/10.1039/d6cp01760f
Biophys Rep. 2026 Jun 30. 12(3): 137-150

Enrichment and amplification of secreted α-synuclein from cellular model and saliva of patients with synucleinopathies.

Wuxian Xu, Mingyue Luan, Zhaoxia Wang, Jianwen Deng, Li Zhu.

  The aggregation and propagation of pathological α-synuclein (α-Syn) are central to the pathogenesis of synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). This study focuses on the enrichment and amplification of secreted α-Syn from cellular models and the saliva of PD patients, utilizing trichloroacetic acid (TCA) precipitation to retain the post-translational modifications (PTMs) and seeding properties of extracellular proteins. By applying TCA precipitation, we successfully concentrated α-Syn from PD patient saliva and cell culture media while preserving critical PTMs (e.g., truncation and phosphorylation) that are essential to amyloidogenicity. Subsequent Western blot (WB) and real-time quaking-induced conversion (RT-QuIC) assays revealed that TCA-enriched α-Syn retained robust prion-like seeding activity, enabling the cross-cellular propagation of pathologically misfolded species. This workflow establishes TCA precipitation as a unique tool for capturing pathologically modified α-Syn from biofluids while maintaining their native seeding capacity. By integrating enrichment and amplification strategies, our findings advance the utility of saliva-based biomarkers for synucleinopathies and provide a translational platform to evaluate therapeutics targeting α-Syn transmission.

Keywords:  Parkinson’s disease; RT-QuIC; Saliva biomarkers; Seeding activity; Synucleinopathies; α-Synuclein

DOI:  https://doi.org/10.52601/bpr.2025.250014
Exp Neurol. 2026 Jun 30. pii: S0014-4886(26)00260-8. [Epub ahead of print]404 115895

Structural dynamics of α-Synuclein: Multi-scale imaging insights into pathological progression across Synucleinopathies.

Huiyi Yang, Zhengming Tian, Jia Liu.

  The misfolding and aberrant aggregation of alpha-synuclein (α-syn) constitute the central pathological hallmark of a spectrum of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A continuous ultrastructural conformational evolution from disordered monomers through toxic oligomers to amyloid fibrils is linked to the formation of Lewy pathology and the progressive functional decline of neurons. This review integrates structural dynamics revealed by multi-scale electron microscopy (EM) techniques-including transmission electron microscopy, immunoelectron microscopy, cryo-electron microscopy (cryo-EM)/cryo-electron tomography, correlative light and electron microscopy, and volume electron microscopy-to systematically delineate the polymorphic spectrum of α-syn assemblies during pathogenesis. This spectrum spans liquid-liquid phase separation-associated condensate precursors and membrane-active toxic intermediates to stable fibrillar and inclusion structures. High-resolution cryo-EM studies have identified disease-specific "structural strains" across synucleinopathies, indicating that genetic variations, disease context, and microenvironmental factors collectively shape distinct atomic conformations that likely correlate with differential toxicity, propagation potential, and clinical phenotypes. EM evidence at the cellular level further elucidates the morphological associations between α-syn aggregates and disruption of synaptic vesicle homeostasis, mitochondrial structural damage, and impairment of the lysosomal-autophagic pathway. Contextualizing these findings within the spatiotemporal progression pattern outlined by the Braak staging system, this article examines the evolution of dominant structural morphologies across disease stages and their pathological significance. It also looks ahead to how in situ three-dimensional imaging technologies are driving a paradigm shift from analyzing "static in vitro structures" to deciphering "dynamic intracellular networks." Finally, the review identifies the core challenge: establishing a verifiable mapping between in vitro-resolved structures and in situ pathological states, and linking structural classifications to specific molecular mechanisms and phenotypic endpoints. This endeavor is crucial for providing a theoretical foundation for developing precise intervention strategies targeting specific pathogenic conformations or propagation nodes.

Keywords:  Lewy pathology; Microscopy; Synucleinopathies; Ultrastructure; α-Synuclein

DOI:  https://doi.org/10.1016/j.expneurol.2026.115895
Front Physiol. 2026 ;17 1873221

When mitochondria lose their fold: matrix proteostasis and stress signaling.

Nils Bertram, Dejana Mokranjac.

  A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.

Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis

DOI:  https://doi.org/10.3389/fphys.2026.1873221
Cell Death Differ. 2026 Jun 30.

Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.

Yiming Wang, Zhuoran Ma, Zongjie Jin, Liang Kou, Nian Xiong, Tao Wang, Yun Xia.

Emerging evidence suggests that microglia exhibit dual regulatory roles in the pathogenesis of Parkinson's disease (PD); however, their precise function in α-synuclein clearance remains incompletely understood. Here, we provide compelling evidence that α-synuclein preformed fibrils (α-syn PFF) impair lysosomal acidification in microglia, leading to defective autophagic flux and disrupted α-syn degradation. This dysfunction further promotes the secretion of microglial extracellular vesicles (EVs), exacerbating disease pathology. Mechanistic investigations uncover that α-syn PFF directly interacts with ATP6V0C, a pivotal V0 subunit of V-ATPase. This interaction sterically hinders V0-V1 domain assembly, disrupting proton pump complex formation and reducing ATP6V0C expression. Functionally, ATP6V0C overexpression rescues lysosomal acidification deficits and facilitates α-syn degradation in vitro, while in vivo, ATP6V0C overexpression alleviates neurotoxicity and reduces phosphorylated α-syn aggregation in α-syn PFF mouse models. Further investigation identifies the PI3K-AKT-mTOR-TFEB pathway as a key regulatory axis of ATP6V0C-mediated lysosomal acidification in microglia. Notably, both TFEB activation and mTOR inhibition restore lysosomal acidity and upregulate ATP6V0C expression, thereby enhancing α-syn clearance. These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression.

DOI: https://doi.org/10.1038/s41418-026-01800-y
iScience. 2026 Jul 17. 29(7): 116399

Connexin 50 mediates disease-relevant alpha-synuclein oligomer propagation and neuroinflammation in neurodegenerative disease.

Nicha Puangmalai, Urmi Sengupta, Nemil Bhatt, Nopparat Suthprasertporn, Fadhl Al-Shaebi, Nikita Shchankin, Jia Yi Liew, Twisha Chatterjee, Dhvani Pansuriya, Ahmet E Balci, Abbigael Aday, Silvana Valdebenito-Silva, Rakez Kayed.

  Connexins, fundamental components of gap junctions and hemichannels, regulate intercellular communication and are emerging neurodegeneration regulators. Primary synucleinopathies and co-morbid synuclein pathologies feature pathological α-synuclein (α-Syn) aggregation, yet mechanisms driving pathogenic α-Syn propagation remain unclear. We identify that connexin 50 (Cx50) interacts with α-Syn aggregates in synucleinopathy-affected human brain tissue. Ex vivo dye uptake assays show markedly elevated hemichannel activity in synucleinopathy mouse brain tissue versus wild-type controls, suppressed by selective Cx50 inhibition. Cx50-expressing cell models exhibit strain-dependent brain-derived α-Syn oligomers (BDSOs) uptake, confirmed pharmacologically. In primary neuron-astrocyte co-cultures from mice expressing human wild-type α-Syn, Cx50 knockdown markedly reduced BDSO uptake and α-Syn aggregation. Cx50 knockdown differentially modulates pro-inflammatory cytokines in BDSO-treated conditions, indicating strain-dependent effects and Cx50-mediated neuron-astrocyte crosstalk in regulating neuroinflammation. This identifies Cx50 as a plausible target for modulating initiation and early spread of α-Syn pathology, supporting Cx50-directed interventions for early-stage disease modification.

Keywords:  molecular biology; neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.116399
Ageing Res Rev. 2026 Jun 29. pii: S1568-1637(26)00215-1. [Epub ahead of print]120 103223

Molecular and environmental drivers of tau post-translational modifications and tau pathology.

Trevor M Price, Autumn E Tucker, Kristen E Funk.

  Tau is an intrinsically disordered protein that functions to support cytoskeletal stability by binding microtubules in neuronal axons. While tau is involved in healthy neuronal function, it can become pathogenic by forming protein aggregates leading to neurologic diseases collectively known as tauopathies, which include Alzheimer's disease, frontotemporal dementia, and chronic traumatic encephalopathy. Post-translational modifications, including phosphorylation, glycosylation, acetylation, methylation, ubiquitination, and protein truncation are molecular drivers that promote tau aggregation and subsequent disease development. There is a growing, but incomplete, understanding of the complex crosstalk that occurs among distinct modifications and how they orchestrate tau pathogenesis in concert. The drivers of tau post-translational modifications are not fully understood, but environmental factors, such as traumatic brain injuries, microbial infections, alcohol abuse, chronic stress, and heavy metal pollutants, increase risk of tau pathology formation. In this article we review the current literature describing the molecular changes that increase tau aggregation propensity, the environmental factors that promote those changes, and the multifactorial crosstalk that modulates tau pathogenesis. Our goal is to outline the biological pathways and molecular factors that drive tau pathogenesis in order to identify potential points of behavioral and/or therapeutic intervention for tauopathies.

Keywords:  Neurodegeneration; Neurofibrillary tangles; Post-translational modifications; Protein aggregation; Tau protein; Tauopathies

DOI:  https://doi.org/10.1016/j.arr.2026.103223
Biochem Soc Trans. 2026 Jul 29. 54(7): 901-913

TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.

Eleni Christoforidou, Emily McFagan, Martha McLaughlin, Majid Hafezparast.

  Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.

Keywords:  ALS; Amyotrophic Lateral Sclerosis; MND; Motor Neuron Disease; TARDBP; TDP-43

DOI:  https://doi.org/10.1042/BST20260896
bioRxiv. 2026 Jun 25. pii: 2026.06.24.734353. [Epub ahead of print]

Genetic Code Expansion, Enzymatic Modification, and C-Terminal Labeling Enable Facile Production of Highly Modified α-Synuclein.

Bernard Abakah, Marie Shimogawa, Paola Miranda-Castrodad, Elizabeth Rhoades, E James Petersson.

α-Synuclein (αS), a protein that plays a central role in Parkinson's disease and related synucleinopathies, is an intrinsically disordered protein (IDP) whose functional interactions and aggregation behavior can be strongly influenced by post-translational modifications (PTMs). Phosphorylation, acetylation, and other PTMs regulate αS's interactions with lipid membranes and binding partners, whereas their dysregulation is associated with aggregation and neuronal toxicity. Despite significant progress through chemical and semi-synthetic approaches, investigating the combinatorial effects of PTMs has remained challenging due to the lack of accessible, site-specific methods. Here, we present an integrated strategy combining genetic code expansion, enzymatic modification, and intein-mediated click chemistry to generate αS variants bearing multiple defined PTMs and a C-terminal fluorescent label. The resulting constructs enable direct evaluation of how individual and combined PTMs influence αS structure, lipid binding, and cellular internalization. Our approach expands the molecular toolkit for dissecting PTM crosstalk in αS and other aggregation-prone IDPs, advancing mechanistic understanding and supporting the development of therapeutic strategies for neurodegenerative disease.

DOI: https://doi.org/10.64898/2026.06.24.734353
Nat Aging. 2026 Jul 03.

Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.

Ju Gao, Devanshi Shukla, Mao Ding, Siyue Qin, Fan Tang, Evelyn Guerrero, Lauren Vicuna, Jiawei Xu, Hongling Li, Masaru Miyagi, Pan P Li, Jingjing Liang, Xinglong Wang.

Autosomal dominant mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is a hallmark of multiple aging-associated neurodegenerative diseases. Despite its pathological role, effective therapies remain limited by the lack of safe, potent molecules targeting TDP-43 neurotoxicity. Here we show that the conserved α-helical region spanning residues 320-340 (conserved region or CR) is a therapeutically actionable target for TDP-43 neurotoxicity. Deletion of CR markedly suppressed TDP-43-induced neuronal death. Structure-based virtual screening identified XL20, a brain-penetrant small molecule that engages CR and confers neuroprotection without affecting TDP-43 splicing activity. XL20 alleviated motor neuron loss, extended survival in TDP-43 p.Ala315Thr ALS mice and enhanced neuronal function in p.Gln331Lys induced pluripotent stem cell-derived human ALS motor neurons. Mechanistically, targeting CR suppressed TDP-43 mitochondrial localization and restored mitochondrial function, likely through liquid-liquid phase separation. Our findings highlight CR as a therapeutic target for TDP-43-associated neurodegeneration and support CR-binding small molecules as therapeutic candidates.

DOI: https://doi.org/10.1038/s43587-026-01166-3
Transl Neurodegener. 2026 Jun 28. pii: 29. [Epub ahead of print]15(1):

Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.

Honglin Zheng, Haiyang Luo, Yongting Lu, Yapei Yuan, Na Zhang, Suying Duan, Zongping Xia, Yuming Xu.

   BACKGROUND: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression.
METHODS: To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent "prion-like" spreading of aggregates.
RESULTS: The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival.
CONCLUSIONS: Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.

Keywords:  Annexin A11; Cerebral organoids; Frontotemporal lobar degeneration; Lysophagy; Lysosomal membrane permeabilization; Prion-like propagation

DOI:  https://doi.org/10.1186/s40035-026-00561-5
Inflammopharmacology. 2026 Jun 27.

A new paradigm in Parkinson's disease: kidney-origin α-synuclein pathology driven by PKC signaling and aurothioglucose.

Kanika Vashisht, Varun Sharma, Mahendra Singh Ashawat, Ashish Baldi, Shiv Kumar Kushawaha.

  Protein Kinase C (PKC), a zinc-dependent signaling enzyme essential for cellular homeostasis, has recently emerged as a critical regulator of α-synuclein (α-Syn) dynamics beyond the central nervous system. Growing evidence suggests that PKC may contribute to α-Syn accumulation in kidney cells through multiple converging mechanisms, including direct phosphorylation of α-Syn, which promotes its aggregation, disruption of the autophagy-lysosome pathway leading to impaired protein clearance, and amplification of oxidative stress and inflammatory responses that enhance α-Syn toxicity. In a paradigm-shifting discovery, recent findings from Wuhan University indicate that Parkinson's disease (PD) pathology may originate in peripheral organs such as the kidneys rather than the brain. Abnormal α-Syn aggregates have been identified in renal tissues of affected individuals, and experimental models demonstrate that compromised kidney function facilitates the systemic spread of these toxic proteins to the brain, potentially initiating neurodegeneration. Notably, α-Syn accumulation has also been observed in patients with chronic kidney disease in the absence of neurological symptoms, suggesting a potential early reservoir function of the kidneys. In this context, aurothioglucose (ATG), a gold-based anti-inflammatory agent, emerges as a promising therapeutic candidate due to its ability to modulate PKC signaling, attenuate inflammation, and restore proteostatic balance. This review highlights a novel kidney-brain axis in PD pathogenesis and proposes PKC-targeted interventions, including ATG, as potential strategies for early disease modification.

Keywords:  Aurothioglucose; Kidney-brain axis; Parkinson’s disease; Protein kinase C; α-synuclein

DOI:  https://doi.org/10.1007/s10787-026-02313-3